Scientists at EPFL's Brain Mind Institute have identified an enzyme that can play a central role in developing a new route of treatment for Huntington's Disease.  The enzyme, called "TBK1", plays a central role in regulating the degradation and clearance of the huntingtin protein and introduces chemical modifications that block its aggregation.

 

We believe that this represents a viable target for the development of possible treatment of Huntington's disease.
Professor Hilal Lashuel


The TBK1 enzyme is a "kinase". In the cell, kinases are enzymes that add phosphate groups to various biomolecules like proteins or DNA. In the world of the cell, phosphate groups are energy-carriers, so adding one essentially "turns on" the receiving molecule.

The researchers found that, when TBK1 adds a phosphate group anywhere in the first 17 amino acids of huntingtin, it inhibits its ability to aggregate. This was the case for both the normal and mutated versions of huntingtin.

In addition, increasing TBK1 levels in cells leads to over-phosphorylation of a specific amino acid (a serine) in the huntingtin chain. This stabilizes the protein and stops it from aggregating.

Finally, TBK1 was also found to signal the cell to degrade and clean out huntingtin before it aggregates. This lowers overall huntingtin levels, which results in reducing aggregate formation inside the cell.

Our work shows that TBK1-mediated increase in phosphorylation and/or promoting mutant huntingtin autophagic clearance represent viable therapeutic strategies for the treatment of Huntington's Disease.
Ramanath Hegde.
We are very excited about these findings. TBK1 has also been shown to regulate the clearance and degradation of proteins implicated in other neurodegenerative diseases. Mutations in TBK1 have also recently been linked to ALS and result in impaired autophagy, which leads to the accumulation of aggregates. Our goal is to find small molecules or drug pathways and to develop these for multiple neurodegenerative diseases.
Professor Hilal Lashuel

 

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